title: Mutational and genetic determinants of λ6 light chain amyloidogenesis.
abstract: Approximately 25% of the λ6 light chains have glycine rather than arginine at position 25, which is an allelic variant of the IGLV6-57 (6a) locus. The Gly25 variant has been shown to decrease the folding stability of the germline λ6 V(L) protein 6aJL2 by 1.7 kcal·mol(-1). In this work, we compared the thermodynamic and fibrillogenic properties of the amyloidosis (AL) derived recombinant (r) V(L) protein AR, which contains the allelic variant Gly25, with those of germline rV(L) 6aJL2-R25G and the λ6 disease-associated V(L) proteins Wil (AL) and Jto (myeloma). Our experiments show that of the four proteins AR is the least stable; forms amyloid fibrils at physiological temperature, pH and ionic strength; has the shortest lag time; and elongates homologous seeds most efficiently. We conclude that the Gly25 allelic variant, together with the somatic mutations, contributes importantly to the extremely low stability and high amyloidogenicity of the AL-derived protein AR.
authors.affiliation: Consorcio Bioquímica de Enfermedades Crónicas, Instituto Nacional de Medicina Genómica (INMEGEN), México.
authors.forename: Martín
authors.initials: M
authors.lastname: González-Andrade
authors.forename: Baltazar
authors.initials: B
authors.lastname: Becerril-Luján
authors.forename: Rosana
authors.initials: R
authors.lastname: Sánchez-López
authors.forename: Héctor
authors.initials: H
authors.lastname: Ceceña-Álvarez
authors.forename: Julio I
authors.initials: JI
authors.lastname: Pérez-Carreón
authors.forename: Ernesto
authors.initials: E
authors.lastname: Ortiz
authors.forename: D Alejandro
authors.initials: DA
authors.lastname: Fernández-Velasco
authors.forename: Luis
authors.initials: L
authors.lastname: del Pozo-Yauner
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000686:Amyloidosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002942:Circular Dichroism; D014644:Genetic Variation / Q000235:genetics*; D007146:Immunoglobulin lambda-Chains / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D017510:Protein Folding; D055550:Protein Stability; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D000682:Amyloid; D007146:Immunoglobulin lambda-Chains; D011994:Recombinant Proteins
keywords: aggregation; amyloid; fibrillogenesis; light chain; misfolding